1. Field of the Invention
The present invention relates to a stable thrombin composition formulated for oral administration which is used for treating hemorrhage in the upper alimentary canal, is stable even at room temperature for long periods of time, has excellent solubility and can be administered orally in a simple manner.
2. Description of the Prior Art
Thrombin is a blood coagulation factor which is well-known and acts directly on fibrinogen to convert it into fibrin in the final stages of blood coagulation. When fibrinogen is present in blood, blood localized at the place of hemorrhage is rapidly coagulated to clot the end of an injured blood vessel. The blood clot mass contracts in the presence of platelets so that the end of the blood vessel is sealed and bleeding stops completely.
Thrombin is prepared by combining thromboplastin with prothrombin prepared from human or bovine blood in the presence of calcium ions. A thrombin composition has been hitherto prepared by filling a vial with a solution of the composition and freeze drying.
Conventional thrombin compositions should be stored below 10.degree. C., because storage at room temperature results in a decrease in physiological activity (The Pharmacopeia of JAPAN, 11th Edition). When this composition is used, it is generally administered either by spraying a solution of the composition in isotonic sodium chloride solution (50 to 1000 units of thrombin per milliliter) or by withdrawing the content from the vial and sprinkling the powder onto the area of bleeding. (The "unit" is defined by NIH.)
Where the composition is used to treat bleeding in the upper alimentary canal, the composition is dissolved in a suitable buffer solution in 200 to 400 units of thrombin per milliliter and the resulting solution is orally administered.
As stated above, however, where the thrombin composition is used to treat the upper alimentary canal, it is administered several times a day at intervals of a few hours. Therefore, it is desirable to develop a composition which can be orally administered by the patient himself in a simple manner.
For this purpose, it is necessary to develop a composition in which the thrombin is stable even when stored at room temperature, even though the composition is not contained in a sealed container such as a vial.
In addition, most vial preparations are used for injection, and that there is a danger that the thrombin composition prepared in a vial might be injected by an inadvertent error in medical institutions. In order to avoid this danger, care such as marking the vial with a special label, has been taken. If no vial were used, however, this special care would be unnecessary. Furthermore, the thrombin composition in a vial has problems in that it is inconvenient for the patient to carry the vial, and handling it is complicated because the vial should be stored below 10.degree. C.
Thrombin compositions for the treatment of hemorrhage in the alimentary canal which permit oral administration in a simple manner are disclosed as prior art in Japanese Patent Application Laid-Open Nos. Hei 1-93536 and Hei 1-121224. The former composition is characterized by enteric coated preparations, and the latter is characterized by containing an alkaline substance to prevent inactivation of thrombin in the stomach. With respect to stability of thrombin compositions during storage, however, these references disclose its stability in a cold place for only 21 days, but fail to disclose any stability at room temperature conditions.